Atherosclerosis is the result of both lipid deposition and chronic vascular inflammation. However, a defined causal role for inflammation in atherogenesis is elusive, largely because of the lack of a clinical success of anti- inflammatory agents in atherosclerosis control. Nevertheless, evidence of the participation of the immune system, especially the key components of innate immunity, Toll-like receptors (TLRs), holds strong in experimental atherosclerosis. Over a dozen TLRs have been identified so far, most of them expressed in atheroma cells, with TLR2 and TLR4 being best documented. Blockade of TLR2 and TLR4 signaling is an intriguing therapeutic approach for atherosclerosis. However, the development of TLR antagonists as therapeutic agents has been surprisingly slow, and no TLR2 or TLR4 antagonists are currently approved for clinic use. Recently, we identified a natural compound Sparstolonin B (SsnB) as an antagonist for TLR2 and TLR4. Our recently published data and new preliminary studies show that: 1) SsnB has potent anti-inflammatory effects on macrophages by selectively blocking TLR2 and TLR4 signaling; 2) SsnB interrupts the recruitment of MyD88 to TLR2 and TLR4; 3) SsnB diminishes the ability of activated arterial endothelial cells to attract monocytes, and decreases arterial smooth muscle cell migration; and 4) SsnB effectively suppresses inflammatory response to lipopolysaccharide in mice. On the basis of these data, we hypothesize that SsnB can attenuate atherogenesis by virtue of its inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose three specific aims: SA1. To test the hypothesis that SsnB attenuates atherogenesis in mice; SA2. To test the hypothesis that SsnB mitigates inflammation in vascular cells by blocking TLR2 and TLR4 signaling; and SA3. To determine the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. The confirmation of the hypothesis will usher the development of SsnB as a new anti-atherogenic agent; it will also provide a pharmacological evidence for the causal role of TLR2 and TLR4 signaling in atherogenesis.